PARP10 promotes cellular proliferation and tumorigenesis by alleviating replication stress

Emily M. Schleicher, Adri M. Galvan, Yuka Imamura-Kawasawa, George Lucian Moldovan, Claudia M. Nicolae

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

During carcinogenesis, cells are exposed to increased replication stress due to replication fork arrest at sites of DNA lesions and difficult to replicate genomic regions. Efficient fork restart and DNA repair are important for cancer cell proliferation. We previously showed that the ADP-ribosyltransferase PARP10 interacts with the replication protein proliferating cell nuclear antigen and promotes lesion bypass by recruiting specialized, non-replicative DNA polymerases. Here, we show that PARP10 is overexpressed in a large proportion of human tumors. To understand the role of PARP10 in cellular transformation, we inactivated PARP10 in HeLa cancer cells by CRISPR/Cas9-mediated gene knockout, and overexpressed it in non-transformed RPE-1 cells. We found that PARP10 promotes cellular proliferation, and its overexpression alleviates cellular sensitivity to replication stress and fosters the restart of stalled replication forks. Importantly, mouse xenograft studies showed that loss of PARP10 reduces the tumorigenesis activity of HeLa cells, while its overexpression results in tumor formation by non-transformed RPE-1 cells. Our findings indicate that PARP10 promotes cellular transformation, potentially by alleviating replication stress and suggest that targeting PARP10 may represent a novel therapeutic approach.

Original languageEnglish (US)
Pages (from-to)8908-8916
Number of pages9
JournalNucleic acids research
Volume46
Issue number17
DOIs
StatePublished - Jan 1 2018

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Carcinogenesis
Cell Proliferation
HeLa Cells
Neoplasms
Clustered Regularly Interspaced Short Palindromic Repeats
ADP Ribose Transferases
Gene Knockout Techniques
Proliferating Cell Nuclear Antigen
DNA-Directed DNA Polymerase
Heterografts
DNA Repair
DNA
Proteins
Therapeutics

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

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PARP10 promotes cellular proliferation and tumorigenesis by alleviating replication stress. / Schleicher, Emily M.; Galvan, Adri M.; Imamura-Kawasawa, Yuka; Moldovan, George Lucian; Nicolae, Claudia M.

In: Nucleic acids research, Vol. 46, No. 17, 01.01.2018, p. 8908-8916.

Research output: Contribution to journalArticle

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